A NEW analysis of Phase III clinical trial data presented at the ACTRIMS Forum 2025 in West Palm Beach, Florida, suggests that tolebrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), may be effective in multiple sclerosis (MS) with chronic active lesions. These paramagnetic rim lesions (PRLs), detected via MRI, are associated with inflammation and ongoing neurodegeneration, contributing to disability accumulation in MS.
The post-hoc analysis examined data from the HERCULES and GEMINI trials, which evaluated tolebrutinib 60 mg once daily in patients with relapsing MS (RMS) and non-relapsing secondary progressive MS (nrSPMS). Investigators assessed whether PRLs at baseline could serve as a biomarker for treatment response and disability progression.
Results showed that 61% of trial participants had PRLs at baseline, consistent with prior MRI-based studies. In both trials, the risk of 6-month confirmed disability worsening (6-mo CDW) increased with a higher number of baseline PRLs in patients receiving placebo or teriflunomide. However, tolebrutinib significantly reduced this risk, particularly in patients with multiple PRLs:
In HERCULES, tolebrutinib reduced 6-mo CDW risk by 54% in participants with four or more PRLs.
In GEMINI, risk reductions were 46% and 49% in participants with 1-3 and ≥4 PRLs, respectively.
Notably, tolebrutinib-treated patients with PRLs had a disability progression risk similar to those without PRLs, suggesting a potential role in mitigating PRL-driven neurodegeneration.
These findings highlight PRLs as a potential biomarker for identifying patients who may benefit most from BTKi therapy. Given that PRLs are resistant to current MS therapies, tolebrutinib’s ability to modulate microglia- and B cell-driven neuroinflammation could represent a significant advance in MS treatment.
As research continues, these insights could shape more personalized treatment strategies, targeting high-risk patients for improved long-term outcomes.
Reference: Oh J et al. Paramagnetic Rim Lesions as a Prognostic and Predictive Biomarker in the Tolebrutinib Phase 3 Trials for Disability Outcomes. Presented at ACTRIMS Forum 2025, West Palm Beach, Florida, USA, February 27 – March 1.
Anaya Malik | AMJ
